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Patented Feb. 13,1951

UNITED STATES PATENT YOFFICE 3 AMINOMETHYL 2 HYDROXY 1,4

NAPHTHOQUINONES AND THEIR PRO- DUCTION Marlin T. Lefller, Lake Blufi,Ill., assignor, by mesne assignments, to Research Corporation, New York,N. Y., a corporation of New York No Drawing. Application March 19, 1946,Serial No. 655,604

Claims.

3-substituted -2-hydroxy 1,4 naphthoquinones and may be represented bythe following formula:

where R represents hydrogen, an alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, amyl, hexyl, decyl, etc., includingsubstituted alkyl groups such as the hydroxy alkyls, aralkyls, etc.,cyclic groups includ'ng alicyclics such as cyclo-hexyl, andheterocyclics such as dioxanyl,

and where the Rs together with the N atom form a heterocyclic ring suchas morpholino, piperidino including alkyl substituted piperidino, etc.

The compounds of the present invention may be prepared by the Well knownMannich reaction. This reaction involves the reaction of an aldehyde andan amine with lawsone (z-hydroxy' -lfl-naphthoquinone) and may beillustrated by'the follow-'- ing example. a I i.

and washed well with cold water.

2 EXAMPLE 2-hydroxy-3 -piperidino-methyZ-1,4-naphthoquione I CH CH OH Toabout 9 grams of piperidine in 100 cc. of

ethyl alcohol is added about 17.4 grams of 2-hydroxy-1,4-naphthoquinone(lawsone). The resulting solution is cooled and stirred and maintainedat about to C. while adding dropwise about 8.5 cc. of 37 per centformalin. After stirring at room temperature for about one-half hour,the reaction mixture is next refluxed on a steam bath for about twohours and then allowed to stand at room temperature over night. Theheavy, deep red precipitate that forms is separated from the reactionmixture by filtration The product obtained i. e., crude2-hydroxy-3piperidinomethyl-1,4-naphthequinone, may be purified byrecrystallization from per cent methanol, yielding orange prisms meltingat about 196- 197 C.

Experiments have demonstrated the 3-piperi- (lino-methyl compounddescribed above to be characterized by low toxicity and to be effectiveagainst certain types of parasitic infections.

With this compound, for examplefiit has been found that avian infectionssuch "as P. Zophurae may be controlled by oral administration at dosagelevels of about? 5 mg. per kg. 3-

Examples of other illustrative compounds of the present invention aregiven in table form below TABLE 3(X) substitutedZ-hydroxy-l,4-naphthoquinone X Nameof 3-substituent Melting Point,",-'C.

CH3--N=(CH3)1 dimethylamino-methyl. 193-194 (decomp).

H v (writ-04m n-butylamino-methyh 157-155;

H CH1l IC H n-amylamino-methyl 159-160 (decomp).

H OH;l ICwH n-decylamino-methyl 148-149 (decomp).

H r OH1 IoHzoH,oH fi-hydroxyethylamino- 168(decon1p). methyl.

H CH l ICH C H benzylamino-methyl 149450 (decomp).

H CH -CH2 CH l IC CH2. cyclohexylamino-methyl 185-190 (decomp);

CH CH2 CHZ O CH2l CH CH S-methyl -1,3 -dioxanyl 195 (decomp).

5-amino-methyl. CH3 CH -O GHQ-CH2 CH -N morpholino-methyl 185 (decomp).

CH CE h CH2CH2 CH-N CHz a-methylpipcridino-methyl 165 (decomp).

CH-Cz CHz-CH:

OHrN CHCH -methylpiperidino-methyl 183.5-184 (decomp).

CHz-CH:

The compounds listed above may be prepared 0 salt formation i. e., theexistence of a zwitteriby the Mannich reaction in accordance with theexample given above by reacting the appropriate amine With formaldehydeand lawsone. The use of dimethylamine in place of piperidine, forexample, Will give the product3-dimethy1aminomethyl-2-hydroxy-1,4-naphthoquinone, which is the firstcompound listed in the above table. The substitution of ethylmethylaminefor dimethylamine similarly will give the product 3-ethylmethylamino-methyl-2-hydroxy1,4-naphthoquinone.

The. compounds of the present invention are amphoteric, being solublein.both acids-and alkalies. I The 2-hydriox y-3rpiperidino-methyl-dArnaphthoquinone product gives a. yellow solution on, as represented bythe formula:

9 h CH2 7 ditions of service.

5 I claim: 1. Compound of the general formula omx wherein X is a basicnitrogen-containing group having its nitrogen attached to the methylenecarbon'and'selected from lower alkyland dialkylamino' groups,cycloalkylamino groups, piperidino, -alky1piperidino, morpholino andmethyl-l,3 dioxanyl-5-amino groups.

2. A. 3 alkylamino methyl 2 -hydroxy- 1,4- naphthoquinone.

3. The product, 3-dimethylamino-methy1-2- hydroxy-1,4-naphthoquinone.

4. A'2-hydroxy-1,4-naphthoquinone' having a piperidino-methylsubstituent at the 3-position.

5. The product, 3 -piperidino-methyl-2-hydroxy-1,4-naphthoquinone.

6. A' 3-alkylpiperidino-methyl-2-hydroxy-1,4- naphthoquinone.

7. The product, 3-a-methy1piperidino-methyl-2-hydr0Xy-1,4-naphthoquinone.

8. The product, 3-' -methylpiperidino-methyl-2-hydroxy-1,4-naphthoquinone.

9. The product of claim 2 where the alkyl is a decyl group.

10.;The method which comprises reacting 2- hydroxy-lA-naphthoquinonewith formaldehyde and a' nitrogen-containing base selected from thegroup consisting of lower alkyland di-alkylamines, cycloalkylamines,piperidine, alkylpiperidines, morpholine, and 5-methyl-1,3-dioxanyl-5-amine and recovering from the reaction product the corresponding3-substituted compound of the general formula OHZX l 6 wherein X is abasic nitrogen-containing group having its nitrogen attached to themethylene carbon and selected from lower alkyland dialkylamino groups,cycloalkylamino groups, piperidino, lalkylpiperidino, morpholino and 5-methyl-l,3-dioxanyl-5-amino groups.

' MARLIN T. LEFFLER.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 1,824,676 Mannich Sept. 22, 19311,913,621 Williams et al June 13, 1933 2,040,039 Bruson May 5, 19362,040,040 Bruson May 5, 1936 2,056,046 Fourneau Sept." 29, 19362,220,834 Bruson et a1. Nov. 5, 1940 2,260,265 Senkus Oct. 21, 19412,284,118 Bock May 26, 1942 2,366,611 Grun Jan. 2, 1945 FOREIGN PATENTSNumber Country Date 422,916 Germany Dec. 15, 1925 673,949 Germany Mar.31, 1939 OTHER REFERENCES Forneau: Chimie et Industrie, vol. 39 (No. 6),pp. 1054 (T) and 1056 (172T), 1938, June, complete article 1051-1061(167T173T).

Schonhofer: Zeit. Physiol. Chem., vol. 274, p. 3 (1942) (completearticle pp. 1-8).

1. COMPOUND OF THE GENERAL FORMULA
 10. THE METHOD WHICH COMPRISESREACTING 2HYDROXY-1,4-NAPHTHOQUINONE WITH FORMALDEHYDE AND ANITROGEN-CONTAINING BASE SELECTED FROM THE GROUP CONSISTING OF LOWERALKYL- AND DI-ALKYLAMINES, CYCLOALKYLAMINES, PIPERIDINE,ALKYLPIPERIDINES, MORPHOLINE, AND 5-METHYL-1,3-DIOXANYL-5AMINE ANDRECOVERING FROM THE REACTION PRODUCT THE CORRESPONDING 3-SUBSTITUTEDCOMPOUND OF THE GENERAL FORMULA